Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acidic pH plays an important role in various pathophysiological states and has been demonstrated to be carcinogenic in animal models. Recent studies have also implicated acidic pH in the development of preneoplastic Barrett's esophagus in human. However, little is known about the molecular mechanism underlying acidic pH-induced carcinogenesis. In the current study, we show that acidic pH, like the topoisomerase II (TOP2) poison VP-16 (demethylepipodophyllotoxin ethylidene-beta-D-glucoside), induces tumors in 9,10-dimethyl-1,2-benzanthracene(DMBA)-initiated mice. The following studies in tissue culture models have suggested that acidic pH acts like a TOP2 poison to induce TOP2-mediated DNA damage: (i) acidic pH induces TOP2-dependent DNA damage signals as evidenced by up-regulation of p53 and Ser-139 phosphorylation of H2AX [a substrate for ataxia telangiectasia mutated (ATM)ATM and Rad3-related (ATR) kinases]; (ii) acidic pH-induced cytotoxicity in tumor cells is reduced in TOP2-deficient cells; (iii) acidic pH increases the mutation frequency of the hypoxanthine phosphoribosyl transferase (HPRT) gene in a TOP2-dependent manner; and (iv) acidic pH induces reversible TOP2-mediated DNA strand breaks in vitro. We discuss the possibility that TOP2-mediated DNA damage may contribute to acidic pH-induced carcinogenesis.
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PMID:Acidic pH induces topoisomerase II-mediated DNA damage. 1269 9

Prostate cancer is the most common noncutaneous malignancy of American men. Although it can be initially treated with androgen deprivation therapy, tumors that relapse become resistant to future hormonal manipulation. We previously found that the multidrug resistance protein (MRP), MRP1, is overexpressed in advanced stage and grade human prostate cancer and is negatively regulated by p53. In this study, we sought to determine whether the cellular accumulation of the antiandrogen flutamide, a drug commonly used in the treatment of prostate cancer, is affected by MRP1 expression. There were significant differences between the wild-type and MRP1-overexpressing cells in efflux and accumulation of flutamide and hydroxyflutamide, its active metabolite. In contrast, transport of dihydrotestosterone was not affected by MRP1. Treating the cells with leukotriene D4, a known MRP1 substrate, or VX-710, an MRP1 modulator, restored flutamide and hydroxyflutamide accumulation. Finally, intracellular glutathione depletion with buthionine sulfoximine or energy depletion using 2-deoxy-D-glucose/sodium azide restored flutamide accumulation to that of parental cells while incubating the cells at 4 degrees C abolished MRP1-mediated transport. In summary, these studies indicate that flutamide and hydroxyflutamide but not dihydrotestosterone are transported by MRP1 and that these findings may contribute to our understanding of resistance to hormone refractory prostate cancer.
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PMID:Effect of the multidrug resistance protein on the transport of the antiandrogen flutamide. 1275 Feb 71

Ulcerative colitis and Crohn's disease (together known as Inflammatory Bowel Disease or IBD) are both associated with increased risk for colorectal cancer. Although it is conventional to emphasise differences between IBD-associated and sporadic colon cancer, such as a lower rate of Adenomatosis Polyposis Coli mutations and earlier p53 mutations, IBD-associated cancer has a similar dysplasia-cancer sequence to sporadic colon cancer, similar frequencies of major chromosomal abnormalities and of microsatellite instability and similar glycosylation changes. This suggests that IBD-associated colon cancer and sporadic colon cancer might have similar pathogenic mechanisms. Because the normal colon is arguably in a continual state of low-grade inflammation in response to its microbial flora, it is reasonable to suggest that both IBD-associated and sporadic colon cancer may be the consequence of bacteria-induced inflammation. We have speculated that the glycosylation changes might result in recruitment to the mucosa of bacterial and dietary lectins that might otherwise pass harmlessly though the gut lumen. These could then lead to increased inflammation and/or proliferation and thence to ulceration or cancer. The glycosylation changes include increased expression of onco-fetal carbohydrates, such as the galactose-terminated Thomsen-Friedenreich antigen (Gal beta1,3GalNAc alpha-), increased sialylation of terminal structures and reduced sulphation. These changes cannot readily be explained by alterations in glycosyltransferase activity but similar changes can be induced in vitro by alkalinisation of the Golgi lumen. Consequences of these changes may be relevant not only for cell-surface glycoconjugates but also for intracellular glycoconjugates.
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PMID:Altered glycosylation in inflammatory bowel disease: a possible role in cancer development. 1282 Jul 18

Apoptosis of lens epithelial cells (LECs) is implicated in the pathogenesis of several types of cataract formation. The high intracellular levels of polyol induce histological change in the LECs, which is considered the earliest event in sugar cataractogenesis. This study was designed to investigate whether high galactose exposure induces apoptosis in LECs during the development of sugar cataract. The effect of an aldose reductase inhibitor, SNK-860, was also examined. We induced sugar cataract in Sprague-Dawley rats by feeding them a 50% galactose-containing diet with or without SNK-860. The percentage of LECs undergoing apoptosis was measured by the terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling (TUNEL) method, and DNA fragmentation analyses were performed. Galactitol levels in the lens epithelium were quantified by gas chromatography. The number of TUNEL-positive cells gradually increased throughout the period of galactose exposure, up to 5 days. DNA fragmentation analysis in LECs of rats fed a galactose-rich diet demonstrated an apparent ladder pattern. SNK-860 reduced the percentage of TUNEL-positive cells, the amount of intracellular galactitol, and the levels of DNA laddering. To explore the mechanism of the apoptotic process, the expression of p53, a potent mediator of apoptosis, was examined. Based on Western blot and real-time reverse transcription-polymerase chain reaction results, the amount of p53-expression increased at both the protein and mRNA levels after galactose exposure, and the increase in p53-expression was inhibited by SNK-860. Based on these results, we concluded that apoptosis occurs in rat lens epithelial cells following galactose exposure. Furthermore, the reduction of apoptosis by aldose reductase inhibitor suggests that this apoptosis is associated with the accumulation of sugar alcohols. It is probable that the mechanism of apoptosis during sugar cataract formation involves the increased expression of p53.
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PMID:Apoptotic cell death in the lens epithelium of rat sugar cataract. 1282 87

Malignant cells characteristically exhibit altered metabolic patterns when compared with normal mammalian cells with increased reliance on anaerobic metabolism of glucose to lactic acid even in the presence of abundant oxygen. The inefficiency of the anaerobic pathway is compensated by increased glucose flux, a phenomenon first noted by Otto Warburg approximately 80 years ago and currently exploited for 2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging in clinical radiology. The latter has demonstrated the glycolytic phenotype is a near-universal phenomenon in human cancers. The potential role of the glycolytic phenotype in facilitating tumor invasion has been investigated through mathematical models of the tumor-host interface. Modified cellular automaton and diffusion reaction models demonstrate protons will diffuse from the tumor into peritumoral normal tissue subjecting nontransformed cells adjacent to the tumor edge to an extracellular pH significantly lower than normal. This leads to normal cell death via p53-dependent apoptosis pathways, as well as degradation of the interstitial matrix, loss of intercellular gap junctions, enhanced angiogenesis, and inhibition of the host immune response to tumor antigens. Transformed cells maintain their proliferative capacity in acidic extracellular pH because of mutations in p53 or some other component in the apoptosis pathways. This allows tumor cells to remain proliferative and migrate into the peritumoral normal tissue producing the invasive phenotype. Mathematical models of invasive cancer based on tumor-induced acidification are consistent with extant data on tumor microenvironment and results from clinical positron emission tomography imaging, including the observed correlation between tumor invasiveness and glucose utilization. Novel treatment approaches focused on perturbation of the tumor microenvironment are predicted from the mathematical models and are supported by recent clinical data demonstrating the benefits of azotemia and metabolic acidosis in survival of patients with metastatic renal cancer. The evolutionary basis for adoption of the glycolytic phenotype during carcinogenesis remains unclear because it appears to confer significant competitive disadvantages on the tumor cells due to of inefficient energy production and expenditure of resources to remove the acid byproducts. We propose that the glycolytic phenotype represents a successful adaptation to environmental selection parameters because it confers the ability to invade. That is, the glycolytic phenotype allows the cell to move from the microenvironment of a premalignant lesion to adjacent normal tissue. There it competes with normal cells that are less fit than the populations within the tumor in a microenvironment of relative substrate abundance. The consequent unrestrained proliferation allows the glycolytic phenotype to emerge simultaneous with the transition from a premalignant lesion to an invasive cancer.
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PMID:The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models. 1287 71

Telomerase activity is repressed in most human somatic tissues during differentiation processes but strongly up-regulated in most human tumors. Regulation of human telomerase activity primarily occurs at the level of transcriptional initiation of the TERT gene, which encodes the catalytic subunit of telomerase. We have generated a novel transgenic mouse model to study the regulation of the human TERT gene promoter in an in vivo system. For this purpose, we have cloned an 8.0-kbp human TERT promoter fragment in front of the bacterial lacZ reporter gene (hTERTp-lacZ), which encodes the beta-galactosidase enzyme. Expression of the reporter gene was monitored by reverse transcription-PCR analysis, 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining of whole mount preparations, and histologic sections. We find that the activity of the human TERT promoter in most normal mouse tissues recapitulates the expression of the hTERT gene in normal human tissues and is under tighter control when compared with the endogenous mouse TERT gene expression. In testis, where highest lacZ expression was observed, the expression of the reporter gene was restricted to the spermatogonial stem cells and the spermatocytes. Intriguingly, we find increased levels of lacZ expression in mammary tumors of hTERTp-lacZ x p53(+/-) bitransgenic mouse mammary tumor model. Thus, this transgenic mouse model provides a suitable in vivo system to analyze the expression of the human TERT gene under physiologic conditions and during tumorigenesis.
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PMID:A novel transgenic mouse model reveals humanlike regulation of an 8-kbp human TERT gene promoter fragment in normal and tumor tissues. 1573 2

Several lines of evidence support that beta-amyloid (Abeta)-induced neurotoxicity is mediated through the generation of reactive oxygen species (ROS) and elevation of intracellular calcium. In this study, we have investigated protective effects of sesaminol glucosides on Abeta-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. Sesaminol glucoside (50-250microg/ml) decreased Abeta(25-35)-induced ROS generation, formation of 8-oxodG, a form of oxidative DNA and elevation of intracellular calcium level concomitant with prevention of apoptotic cell death dose dependently. Sesaminol glucoside (50-250microg/ml) also effectively decreased Abeta1-42 and ADDL form of Abeta1-42 as well as the combination of H2O2 with FeSO4-induced cell damages. In mechanistic study, sesaminol glucosides attenuated Abeta25-35-induced activation of redox transcription factor nuclear factor-kappaB NF-kappaB through inhibition of p50 translocation and IkappaB phosphorylation, and blocked NF-kappaB-dependent luciferase activity in addition to the inhibitory effect on Abeta25-35-induced activation of ERK kinase signal pathway. Consistent with the inhibitory effect on Abeta25-35-induced stress-induced cell death, sesaminol glucosides decreased expression of pro-apoptotic gene p53, and Bax and caspase-3, but enhanced expression of anti-apoptotic Bcl-2. Moreover, the protective effects of sesaminol glucoside on Abeta25-35-induced ROS generation, NF-kappaB activation and cell death were further enhanced with glutathione. This study therefore suggests that sesaminol glucosides have protective effect on Abeta-induced neuronal cell death, and its effect may be through antioxidative property.
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PMID:Effect of sesaminol glucosides on beta-amyloid-induced PC12 cell death through antioxidant mechanisms. 1588 33

4-Demethyl-picropodophyllotoxin 7'-O-beta-D-glucopyranoside (4DPG), a new podophyllotoxin glucoside, was isolated from the rhizomes of Sinopodophyllum emodi (Wall.) Ying and showed cytotoxic effects in human carcinoma cells. Among the target cells (HeLa, A2 and SH-SY5Y), the cytotoxic effects of 4DPG showed dose- and time-dependency. Furthermore, the cervical carcinoma cell line, HeLa, was more sensitive to 4DPG. Flow cytometric analysis demonstrated the presence of apoptotic cells with low DNA content, a decrease of cell population at the G1 phase, and a concomitant increase of cell population at the G2/M phase. 4DPG also caused DNA fragmentation in HeLa cells. Treatment with 0.1 microM 4DPG increased p53 expression and Bax/Bcl-2 ratio in HeLa cells, as well as in A2 cells. These results suggested that 4DPG-induced apoptosis might be through a p53-dependent pathway.
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PMID:Apoptosis induced by one new podophyllotoxin glucoside in human carcinoma cells. 1592 73

The glycolytic inhibitor 2-deoxy-D-glucose (2-DG) has been shown to enhance the cell death induced by radiation and other DNA damaging agents selectively in cells with high rates of glycolysis, like cancer cells. While energy linked modification of DNA and cellular repair processes have been suggested as possible mechanisms of sensitization, other effects such as global stress response cannot be excluded. In this pilot study, we have investigated the effect of 2-DG and radiation on the transcriptome in an attempt to elucidate how 2-DG impacts gene expression in undamaged verses irradiation (IR) damaged cells using a human malignant glioma cell line, U-87. Exponentially growing U-87 cells were exposed to various combinations of 2-DG and X-rays and total RNA was isolated four hours after exposure. Gene expression changes were elucidated using Affymetrix GeneChips. As expected, U-87 cells treated with 2-DG showed activation of several endoplasmic reticulum stress response genes. Selective RT-PCR and Western blotting confirmed these gene alterations. Given that glucose deprivation leads to p53 activation and 2-DG led to activation of p53 response genes in our present study (e.g., PMAIP1 and GADD45A), we examined the impact of transient p53 knockdown and observed that induction of PMAIP1 and GADD45A appear to be via p53-independent mechanisms. The majority of gene alterations seen with IR-treatment alone were consistent with previous reports. While most gene alterations seen with 2-DG and IR dual treatment were confirmed in the gene profiles seen with individual (2-DG or IR) treatments, several genes appeared differentially regulated between IR and 2-DG (e.g., DUSP8, IL8, GADD45B). Additionally, gene expression patterns suggested alterations in cell cycle regulation, apoptosis, and cytokine signaling pathways. Taken together, this study provides new insights into how the transcriptome of tumor cells are likely to be affected by a combined stress caused by IR and 2-DG.
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PMID:Altered gene expression induced by ionizing radiation and glycolytic inhibitor 2-deoxy-glucose in a human glioma cell line: implications for radio sensitization. 1688 Jul 34

Several studies have revealed the diagnostic value of fluorodeoxyglucose-positron emission tomography for breast carcinomas. However, breast carcinomas display considerable variation in 18F-labeled 2-fluoro-2-deoxy-D-glucose uptake, and few papers have reported the clinical utility of the standardized uptake values (SUV). The purpose of this study is to investigate the relationship between SUV assessed by positron emission tomography (PET) and the clinicopathological characteristics of breast carcinoma. We reviewed 52 breast carcinomas of 45 patients presented at our department between January 2004 and July 2005. We compared the histopathological findings of the breast carcinomas with the preoperative SUV. Of the 52 breast carcinomas, 49 (94%) were detected by preoperative PET. A positive correlation was found between the SUV and tumor size (P < 0.01), histological grade (P < 0.01), the expression of the estrogen receptor (P < 0.001), progesterone receptor (P < 0.01), and p53 (P < 0.01). The number of metastatic axillary lymph nodes (r = 0.73; P < 0.0001) and the MIB-1 labeling rates (r = 0.5; P < 0.01) correlated with the SUV of the breast carcinomal. No relationship existed between the SUV and the following: histological tumor types (P = 0.07), human epidermal growth factor receptor-2 status (P = 0.10), and the presence of metastatic lymph nodes (P = 0.10). The SUV of the breast carcinomas correlate with several histopathological and immunohistochemical prognostic factors. We can obtain information on the degree of malignancy of the carcinoma and prognostic factors by preoperative PET examination.
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PMID:Standardized uptake values for breast carcinomas assessed by fluorodeoxyglucose-positron emission tomography correlate with prognostic factors. 1809 53


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